Neoplasia is a disease characterized by an abnormal proliferation of cell growth known as a neoplasm. Neoplasms may manifest in the form of a leukemia or a tumor, and may be benign or malignant. Malignant neoplasms, in particular, can result in a serious disease state, which may threaten life. Significant research efforts and resources have been directed toward the elucidation of antineoplastic measures, including chemotherapeutic agents, which are effective in treating patients suffering from neoplasia. Effective antineoplastic agents include those which inhibit or control the rapid proliferation of cells associated with neoplasms, those which effect regression or remission of neoplasms, and those which generally prolong the survival of patients suffering from neoplasia. Successful treatment of malignant neoplasia, or cancer, requires elimination of all malignant cells, whether they are found at the primary site, or whether they have extended to local-regional areas or have metastasized to other regions of the body. The major therapies for treating neoplasia are surgery and radiotherapy (for local and local-regional neoplasms) and chemotherapy (for systemic sites) [45].
The ideal antineoplastic drug would target and destroy only malignant neoplastic cells, without producing toxic or adverse effects on normal, nonmalignant cells. Malignant neoplastic cells usually have a shorter cell cycle than nonmalignant cells. In contrast, most nonmalignant cells have a larger percentage of cells in the G0 resting phase, resulting in a smaller proliferation fraction than that which is found in malignant cells. Accordingly, cellular kinetics are important in devising effective antineoplastic drug regimens. Many antineoplastic drugs are effective only if cells are in the cell cycle, and some drugs only work during a specific phase of the cell cycle. Cellular kinetics also may influence the dosage schedules and timing of treatment [45].
The failure of chemotherapeutic drugs in vivo, when efficacy has been documented in vitro, has led to extensive studies of drug resistance. One identified mechanism, pleiotropic resistance (or multidrug resistance), results from several genes that limit drug dwell and function in malignant neoplastic cells in the patient. Attempts to alter this resistance have not been successful. Thus, while single-drug chemotherapy has achieved cures in a limited number of cancers, regimens utilizing multiple drugs having different mechanisms of action, intracellular sites of activity, and toxicities (to reduce the potential compounding of toxicity) may provide significant cure rates [45].
Paclitaxel is a natural diterpene that has been isolated from several species of yew trees. It is also available commercially under the registered trademark Taxol [47]. Paclitaxel is an antimitotic agent (spindle poison) that enhances the assembly of microtubules from tubulin dimers, and stabilizes them against depolymerization [1, 47]. This stability results in the inhibition of normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions [47]. Paclitaxel is well-known as an effective antineoplastic chemotherapeutic agent. In fact, paclitaxel (Taxol) has been used with success in the treatment of leukemias and tumors, particularly breast, lung, and ovarian carcinomas [2], and malignant melanoma. Despite its considerable clinical success, there are a number of serious disadvantages to the use of paclitaxel. One problem, for example, is related to the extreme hydrophobic nature of the compound, which has made its formulation a continual problem. Paclitaxel also produces side-effects, including alopecia, arthralgia, myalgia, myelosuppression, and neuropathy [45]. Furthermore, the development of multidrug resistance in human tumors, as a result of overproduction of P-glycoprotein, may reduce the efficacy of paclitaxel in some patients.
The low aqueous solubility of paclitaxel and the development of clinical resistance to this antineoplastic agent have led to a search for new small-molecule compounds that may have an efficacy that is greater than, or comparable to, that of paclitaxel. Ideally, the new compounds would be more soluble in aqueous solvents, and would be poor substrates for P-glycoproteinxe2x80x94a known mediator of paclitaxel (Taxol) resistance [9]. The development of clinical resistance to paclitaxel also has highlighted the need for new combinations and schedules for these new antineoplastic agents. Indeed, while paclitaxel has had clinical success, both as a single agent and in combination with cisplatin [21], its use in combination with other antineoplastic agents is currently under intense evaluation, particularly for the treatment of advanced or recurrent cancers which are refractory to standard chemotherapy [22].
Classically, synergy is defined as the joint action of two or more drugs which produces a greater-than-additive therapeutic effect when compared to the therapeutic efficacy of each drug alone. Many combination therapies now being tested use drugs with dissimilar mechanisms of action, based on the rationale that targeting two independent pathways will result in enhanced cytotoxicity, whether additive or synergistic [23-26]. Nevertheless, one must not discount the use of agents with similar mechanisms of action or similar molecular targets [27-29].
Discodermolide is a natural lactone that has been isolated from the marine sponge, Discodermia dissoluta. Like paclitaxel, discodermolide is known to have activity against mammalian cancer cells. Discodermolide has a mechanism of action similar to that of paclitaxel: it has the ability to stabilize microtubules by binding to the same or overlapping sites on xcex2-tubulin, thereby resulting in cell death and mitotic arrest [11]. Moreover, discodermolide has been predicted to be one hundred times more soluble than paclitaxel (Taxol), and to have a reduced affinity for P-glycoprotein [13].
The present invention is predicated on the surprising discovery that administration of Taxol in combination with discodermolide produces a synergistic antineoplastic effect. This discovery was unexpected, as the prior art suggested that combination chemotherapy using two drugs which bind to identical or overlapping sites on the same target generally results in additivity or antagonism. On the basis of this finding, the present invention provides a method of treating neoplasia in a subject in need of treatment, by administering to the subject an amount of paclitaxel effective to treat the neoplasia, in combination with an amount of discodermolide effective to treat the neoplasia, wherein a synergistic antineoplastic effect results.
Also provided by the present invention is a synergistic combination of antineoplastic agents, comprising an effective antineoplastic amount of paclitaxel and an effective antineoplastic amount of discodermolide.
Additional objects of the present invention will be apparent in view of the description which follows.